Human Rhinoviruses (HRV) cause approximately one third of the 60 million cases of "common cold" each year in the US and therefore are one of the most economically important human diseases of developed countries. Although rhinoviruses are not generally considered "killer" viruses, more recent studies have shown that rhinoviruses are a significant source of hospitalization for those with asthma and chronic pulmonary diseases. The large number of HRV serotypes (>100) stand as a major barrier to vaccine development. However, three past and recent developments suggest that the design of a first generation rhinovirus vaccine may now be possible. First, in vitro evolutionary escape experiments indicate that both monoclonal and polyclonal antibodies made to the HRV capsid act similarly and repeatedly result in rather narrow and similar range of amino acid changes in the capsid of the virus. Second, serological mapping data suggest the host response is largely restricted to immunodominant epitopes located in the most highly variable regions of the capsid flanking the conserved cellular receptor-binding region. Third, a unique small panel of monoclonal antibodies has been shown to neutralize across multiple serotypes. Thus, it is possible that epitopes exist in the virus that can induce more broadly protective antibodies, but are not readily seen by the immune system. Finally, in preliminary studies with the related picornavirus of ungulates, Foot and Mouth Disease Virus, Immune Refocusing mutations introduced into just one of four immunodominant antigenic sites, the GH-loop of VP1, resulted in an antigen that stimulated cross-neutralizing antibodies. We propose 1) to design and produce a panel of HRV39 vaccine candidates with mutational changes to immunodominant epitopes;2) to test the candidates for stimulation of cross-neutralizing antibodies;and 3) to investigate delivery systems for "native- like" capsid protein folding and efficient antigen presentation to the immune system. PUBLIC HEALTH RELEVANCE: Human rhinoviruses (HRVs) are a leading cause of the common cold and an increasingly recognized cause and/or exacerbater of asthma and chronic pulmonary disease. Due to the large number of serotypes, efforts to develop a vaccine have been discouraging. Recent advances in understanding how pathogens utilize highly variable antigenic sites to misdirect the immune system from responding to more highly conserved epitopes have led to the development of the Immune Refocusing Technology for novel vaccine design. We propose to apply this Technology to redirect the immune system to recognize cross-reactive epitopes on HRV39. Sera from mice immunized with the vaccine candidates will be assessed for enhanced cross-reactive antiviral activity against heterologous serotypes. The development of a broadly protective HRV vaccine would result in enormous improvements in health status and have an immediate impact on health-related economic savings.